Palladium catalysis enables cross-coupling–like S _N 2-glycosylation of phenols

Abstract

Despite their importance in life and material sciences, the efficient construction of stereo-defined glycosides remains a challenge. Studies of carbohydrate functions would be advanced if glycosylation methods were as reliable and modular as palladium (Pd)-catalyzed cross-coupling. However, Pd-catalysis excels in forming sp 2 -hybridized carbon centers whereas glycosylation mostly builds sp 3 -hybridized C–O linkages. We report a glycosylation platform through Pd-catalyzed S N 2 displacement from phenols toward bench-stable, aryl-iodide–containing glycosyl sulfides. The key Pd(II) oxidative addition intermediate diverges from an arylating agent (Csp 2 electrophile) to a glycosylating agent (Csp 3 electrophile). This method inherits many merits of cross-coupling reactions, including operational simplicity and functional group tolerance. It preserves the S N 2 mechanism for various substrates and is amenable to late-stage glycosylation of commercial drugs and natural products.

Harnessing Multistep Chalcogen Bonding Activation in the α-Stereoselective Synthesis of Iminoglycosides

“…Subsequently, we designed a competitive experiment where an equal molar of p -bromophenol acceptor 2x (p K a ∼ 9.37) and p -methoxyphenol acceptor 2y (p K a ∼ 10.4) with distinctive differences in their p K a were allowed to react parallelly in the same pot with the same glycosyl donor 1a (Figure B) . Since the ratio of both iminoglycosides ( 3x : 3y ) formed in this experiment can be used to estimate the ratio of the rate constants of both competing reactions, this experiment could illuminate whether the acceptor’s acidity mechanistically influences the rate-limiting step.…”

Synthesis of Glycoconjugates through Chlorooxime–Thiol Conjugation

“…Conventional methods to introduce glycans are the glycosylation of sugar anomeric carbon using nucleophilic acceptors or through radical pathways. , Representative examples include the O - or N -glycosylation of peptides at the hydroxyl group of serine and threonine or the amido group of asparagine side chains. Recently, S -glycosylation at cysteine thiol as the nucleophile has received extensive attention (Scheme A).…”

Anion‐Bridged Dual Hydrogen Bond Enabled Concerted Addition of Phenol to Glycal

“…Furthermore, glycosidic bonds of related products are considerably labile in acidic media. To date, three strategies have been employed to construct phenolic 2‐deoxyglycosides, which involve arylation of anomeric hydroxyl groups, [ 5 ] nucleophilic substitution of glycosyl donors containing leaving groups at anomeric center, [ 2 , 6 ] and direct addition of phenol to glycals. [ 7 ] (Figure 1B ).…”